The cells that compose the epithelium are constantly renewed. To maintain homeostasis in an adult tissue, cell proliferation must be tightly regulated, yet how this is controlled is not fully understood. When this balance is lost and too many cells accumulate, epithelial cancers (or carcinomas) arise. In particular, squamous cell carcinoma (SCC) is the second most common type of skin cancer and its incidence increases with age. Our lab is investigating the role of CD98hc, a dual function transmembrane protein, in epidermal tumor formation.

Epithelial cells rest on a basal membrane composed of highly organized network of extracellular matrix (ECM) proteins. Tumor formation greatly depend on cell adhesion, migration and proliferation which are regulated by both ECM and integrins, a family of cell-surface receptors that interact with ECM proteins. Integrins function as bi-directional signaling molecules.

CD98, originally identified as the 4F2 antigen, is highly expressed in keratinocytes. Its expression also correlates with increased morphological grade and worsened prognosis of tumors, independent of their tissue of origin. CD98 is a heterodimer of a common heavy chain (CD98hc, SLC3A2), and one of several light chains (CD98lc) that each has multiple membrane spanning domains. CD98hc has two main functions: amino acid transporter (via its interaction with a CD98lc) and integrin signaling modulator (via its interaction with β integrins). Its knock-out is embryonic lethal.

The CD98hc-integrin complex plays a crucial role in cell behavior that depends on cell proliferation, migration and survival. Besides, the CD98 heterodimer (heavy chain and light chain) contributes to efficient amino-acid transport, which is vital for cell survival and proliferation.

Our work aims at determining how CD98 interactions contribute to epidermal homeostasis and tumorigenesis.

Thus, on one hand, we will use the CD98hcfl/fl murine line previously generated to determine the role of CD98hc in epidermal homeostasis and skin cancer in vivo. On the other hand, we will decipher the cellular and molecular events resulting from CD98hc deletion in vitro.

The proposed work will revolve around 3 main axes :

1) Determine the role of CD98hc in skin homeostasis and tumorigenesis in vivo